Method and apparatus for heating inflammed tissue

ABSTRACT

The present invention relates to methods for treating inflammation in body tissues. More specifically, certain disclosed methods relate to selectively inducing apoptosis in inflammatory immune cells by heating cells for a sufficient time and at a sufficient temperature to induce programmed cell death. The disclosed stents can be placed in contact with the inflammatory cells and heated under controlled conditions. The disclosed apparatus and methods are particularly suitable for treating athersclerotic plaques.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of 35 U.S.C. 111(b)Provisional application Serial No. 60/114,326 filed Dec. 31, 1998, andentitled Ultrasonically Heated Stent. The present application is alsorelated to patent application Ser. No. 09/303,313 entitled HeatTreatment of Inflammed Tissue which is a continuation of U.S. Pat. No.5,906,636.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not applicable.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The present invention generally relates to methods for treatinginflammed tissue. More particularly, the invention relates to stents fortreating vessels and other annular organs that are capable of beingselectively heated by an external source of radiation and oftransferring that heat to surrounding tissue. The invention also relatesto methods of making and using such heating stents to apply low-levelheat to inflammed tissue

[0005] 2. Description of Related Art

[0006] Coronary artery disease is a leading cause of death inindustrialized countries. It is manifested by athersclerotic plaques,which are thickened areas in vessel walls. A plaque is an accumulationof cholesterol, proliferating smooth muscle cells and inflammatory cellscovered by cellular secretions of collagen that form a cap over theplaque in the vessel wall. Macrophages migrate into and accumulate in aplaque causing inflammation. Inflamed plaques are most susceptible toruptures and the formation of blood clots. Falk, E. (1995).

[0007] Atherosclerotic plaques are thought to develop in response toirritation or biochemical damage of the endothelial cells that lineblood vessel walls. Agents that are known to damage these cells includecigarette smoke, high serum cholesterol (especially in the form ofoxidized low density lipoprotein), hemodynamic alterations (such asthose found at vessel branch points), some viruses (herpes simplex,cytomegalovirus) or bacteria (e.g., Chlamydia), hypertension, and someplasma hormones (including angiotensisn II, norepinephrine) andhomocysteine. Atherosclerotic plaques grow slowly over many years inresponse to the cumulative injury of endothelial cells. Ross (1993),Berliner (1995).

[0008] Typically, several dozen plaques are found in arteries afflictedwith this disease. It is the rupture of these plaques that brings aboutthe terminal stage of the disease. The rupture causes a large thrombus(blood clot) to form on the inside of the artery, which may completelyocclude the blood flow through the artery, thereby injuring the heart orbrain. Falk, E. (1995).

[0009] In most cases of terminal coronary artery disease, only one ofseveral plaques ruptures. Rupture typically is caused by inflammatorycells, primarily macrophages, that lay beneath the surface collagenlayer of the plaques. These cells release enzymes that tend to degradethe cap. Once a plaque ruptures, blood clots are formed and it is theseclots that are believed to be responsible for over one half of all heartattacks and stokes. Falk, E. (1995); Buja (1994).

[0010] Techniques have been developed to identify those plaques that aremost likely to rupture because of inflammation. See U.S. patentapplication Ser. No. 08/717,449, which is specifically incorporated byreference herein. The most common treatment for these plaques ispercutaneous transluminal coronary angioplasty (PTCA), e.g., balloonangioplasty. Frequently, however, injury to the vessel wall anddisruption of the plaque core occur during restoration of vesselpatency. The rapid proliferation of smooth muscle cells in response todamage and inflammation induced in the intimal and medial layers of thevessel wall occurs as part of the body's attempt to heal the “wound” tothe vessel. This leads to neointimization and remodeling of the vesselwall and restenosis. Restenosis is defined as the reclosure of apreviously stenosed and subsequently dilated peripheral or coronaryvessel. Blood clots may form as a result of the spillage of plaquecontents and due to triggering of the natural clot-forming cascade ofthe blood, further contributing to restenosis at the treatment site.Within weeks to months after PTCA, many individuals develop restenosisat the angioplasty site. Various approaches to balloon catheterangioplasty have been introduced, however each has failed at preventingpost-angioplasty restenosis. Some of these include atherectomy devices,laser and thermal ablative devices and stents, examples of which arewell known by those working in the field.

[0011] Apoptosis

[0012] It is clear that in many cases balloon angioplasty causescellular injury and only temporarily eliminates the danger from aninflamed plaque until the advent of a secondary inflammatory response.Casscells (1994).

[0013] It has been shown that macrophages have a life span of only abouta week or two in the vessel wall. Katsuda (1993). Typically, monocytesenter the atherosclerotic plaque, divide once, and contribute to plaquedevelopment by their ability to oxidize low density lipoproteincholesterol and to release factors which cause smooth muscleproliferation and angiogenesis. The cells then undergo apoptosis, whichis an active process of programmed cell death. This process differs fromnecrosis in that apoptosis requires the expenditure of energy, and thesynthesis of new RNA and proteins in all but the inflammatory cells, theactive cleavage of DNA and the shrinkage and involution of the cell withvery little inflammation. Steller (1995); Nagata (1995); Thompson(1995); Vaux (1996).

[0014] Apoptosis is a form of programmed cell death in which the dyingcells retain membrane integrity and are rapidly phagocytosed anddigested by macrophages or by neighboring cells. It occurs by means ofan intrinsic cellular suicide program that results in DNA fragmentationand nuclear and cytoplasmic condensation. The dead cells are rapidlycleared without leaking their contents and therefore little inflammatoryreaction follows. It can be induced by the withdrawal of growth factorsand to some extent by factors which can also cause necrosis such asextreme lack of oxygen or glucose, heat, oxidation and other physicalfactors.

[0015] Previously no method was known for selectively inducing apoptosisin macrophages or other inflammatory cells in a blood vessel withoutalso inducing apoptosis in beneficial endothelial cells. Known methodsfor inducing apoptosis were systemic, including treatments withchemicals and elevated temperatures. Such methods are not useful astherapeutic methods because of the risk that apoptosis will develop inhealthy tissue.

[0016] A number of studies have shown that heat can induce programmedcell death. Kunkel (1986) have found that indomethacin inhibitsmacrophage synthesis of prostaglandin but enhances macrophage productionof TNF-I, which suggests that heating may have advantages overindomethacin as an anti-inflammatory treatment. Preventing the synthesisof prostaglandin, which serve as feedback inhibitors of macrophagefunction, limits the anti-inflammatory utility of indomethacin andpresumably other inhibitors of cyclooxygenase. Field and Morris (1983)surveyed many cell types and found that the time needed to kill cells at43° C. varied from four minutes in mouse testis, to 32 minutes in rattumor in vivo, to 37 minutes for mouse jejunum, to 75 minutes for ratskin, 210 minutes for mouse skin and 850 minutes for pig skin. Numerousother cell types were also studied. They observed that, above 42.5° C.,an increase of 1° C. produces a similar effect as doubling the durationof heat exposure. Wike-Hooly (1984) found that a low pH enhancedhyperthermic cell killing, as did a low glucose or insulin exposure andthat nitroprusside also increased the cell mortality caused byhyperthermia. Raaphorst (1985) and Belli (1988) studied Chinese hamsterlung fibroblasts and found that 45° C. heat and radiation weresynergistic in cell killing. Raaphorst (1985) also found S-phase to beheat-sensitive and least radiosensitive, while in G1 and G2 the oppositewas true. Klostergard (1989) found that cytotoxicity of macrophages wasdecreased by heating to 40.5° C. for 60 minutes. Westra and Dewey (1971)found that in CHO cells S phase was more sensitive to heating to 45.5°C. than was G1 phase. M phase was intermediate. In contrast, radiationkilled cells preferentially in phases G1 and M1. Fifty percent ofasynchronous (cycling) CHO cells were killed by a 20 minute heattreatment at 43.5° C. Freeman (1980) found that the sensitivity of CHOcells to 41° C. to 45.5° C. was increased with acidosis and thatthermotolerance was induced by exposure to 42° C. for 250 minutes.Haverman and Hahn (1982) used an inhibitor of oxidative phosphorylationand found that CHO cells were thereby more prone to heat-induced deathusing 43° C. for one hour. Preheating, however, led to tolerance. Theseexperiments could not determine whether hyperthermia increased ATPutilization or inhibited its synthesis. Gerweck (1984) found that CHOcells were more easily killed by 44° C. (20% died after a 15-minuteexposure) when ATP was depleted by hypoxia and hypoglycemia, but neithercondition alone had an effect. Lavie (1992) found that peritonealmacrophages from older mice tend to die at 42.5° C. for 20 minutes butnot macrophages from younger mice. Papdimitriou (1993) found that mostperitoneal murine macrophages undergo apoptosis with a five-hourexposure to 41° C., but few entered apoptosis at 30° C. Most circulatingmonocytes did not undergo apoptosis at 41° C., with a five-hourexposure. Mangan (1991) reported that TNF alpha and interleukin-1 betaprevent macrophage apoptosis. Chen (1987) reported that heat in therange of 41° C. to 43° C. stimulated macrophage production ofprostaglandins. Prostaglandins serve to suppress macrophage productionand phagocytosis. Heat did not decrease prostaglandin release from tumorcell line or from fibroblasts. They found that macrophage death began at41° C. with a four-hour exposure. A six-hour exposure to 43° C. killedhalf the macrophages. Ensor (1995) found no macrophage cell death aftersix hours at 40° C., (vs. 37° C.) but at 43° C. only 4% of cells wereviable at six hours. O'Hara (1992) found that bone marrow macrophagessurvive 15 minutes at 45° C. if they have been preheated for 110 minutesto 42.5° C.

[0017] Fouqueray (1992) found that exposing rat peritoneal macrophagesto 39° C. to 41° C. for 20 minutes decreased synthesis of IL-1 andTNF-I. Circulating monocytes were less sensitive to heat than glomerularor peritoneal macrophages. This degree of heating did not kill themacrophages. Hamilton (1995) found that the cancer drug bleomycinblocked expression of HSP-72 in human alveolar macrophages in responseto exposure to 39.8° C. This was a relatively specific effect sincethere was no change in overall protein synthesis and, moreover, theeffect appeared to be post-transcriptional, since there was no change inmRNA levels for HSP-72. The bleomycin exposure did not cause muchnecrosis, but it caused marked DNA fragmentation characteristic ofapoptosis. Wang (1995) found that induction of HSP-72 prevented necrosisin human endothelial cells exposed to activated neutrophils. Theactivated neutrophils caused necrosis of endothelial cells that had beenexposed to 30 to 60 minutes of heat shock at 42° C., an exposure whichby itself did not induce necrosis or apoptosis. Wang (1997) found thatendothelial cells did not go to apoptosis with a 45-minute exposure to42° C. or with exposure to TNF-I, but exposure to both did triggerapoptosis. TNF-I resulted in generation of reactive oxygen species,which the authors believe may be required, together with heat shock, toinduce apoptosis in endothelial cells. Kim (1997) found that nitricoxide protected cultured rat hepatocytes from TNF-I induced apoptosis bymeans of inducing HSP-70. Belli (1963) observed that heating enhancescell susceptibility to radiation killing.

[0018] Cytokines are also known to influence apoptosis in macrophagesand other leukocytes. William (1996) found that apoptosis in neutrophilswas promoted by heat, TNF-I, or endotoxin but inhibited by LPS, GMCSFand IL-2. Biffl (1996) found that IL-6 also delayed neutrophilapoptosis. Prins (1994) found in human fat tissue explants adipocytesunderwent apoptosis within 24 hours of a 60-minute exposure to 430C andthen underwent phagocytosis, suggesting that at least some macrophagessurvived longer than some adipocytes. O'Hara (1992) showed thatgranulocyte-macrophage precursors take longer (T_(1/2)=36 min.) tobecome heat-tolerant than do stem cells or erythrocyte precursors frombone marrow. Verhelj (1996) found that 50 percent of confluent,nondividing, bovine aortic endothelial cells underwent apoptosis by 12hours at 43° C., versus 41° C. for dividing human monoblastic leukemiaof the U937 line, but this difference could well be attributable to thedifference in age of the cells, cycling rate or species. D. Elkon and H.E. McGrath (1981) presented some evidence that granulocyte monocyte stemcells do not take as long as other cells to be killed at a temperatureof 42.5° C. Blackburn (1984) reported that circulating monocyteprecursors are more sensitive to heat than are those from bone marrow.Kobayashi (1985) reported that granulocyte-macrophage progenitor cellswere more sensitive to 60 minutes at 42° C. when the marrow wasregenerating (during cell division) than when it was stationary, butthis is a finding in all cell types. Cohen (1991) found no difference inheat tolerance of epithelial cells and airway macrophages, as measuredby immediate release of LDH and chromium-51.

[0019] A number of studies have examined the relationship between heatshock and cell killing. Nishina (1997) found that the stress-activatedprotein kinases (also known as the Jun N-terminal kinases) are activatedin response to heat shock and other cell stresses. A knockout of one ofthese genes (SEK-1) resulted in fewer CD4+, CD8+ thymocytes. Pizurki andPolla (1994) found that cAMP increased synthesis of heat-shock proteinsin heated macrophages. Reddy (1982) found that heat shock of murinemacrophages increased their production of superoxide but did not changetheir production of hydrogen peroxide or their microbicidal activity.Sivo (1996) found that heat shock acted in a fashion similar toglucocorticoids in inhibiting mouse peritoneal macrophages and increasedthe transfer of glucocorticoid receptors to the nucleus. Snyder et. al(1992) found that mouse peritoneal macrophages synthesized heat-shockproteins (HSPs) maximally after a 12-minute exposure to 45° C.; HSPswere only found two to six hours after heat treatment. They found noHSP-70 at 42° C. or 43° C. At 2 and 24 hours after heating, phagocytosiswas normal. They did not mention whether macrophages entered apoptosiswith this treatment and that the same treatment (12 minutes at 45° C.)decreased TNF alpha and IL-1 RNA synthesis in mouse peritonealmacrophages. Pizurki et. al (1994) reported that circulating humanmonocytes express HSPs two hours after 20 minutes of exposure at 45° C.and that HSP expression was enhanced in the presence of cAMP andunaffected by indomethacin.

[0020] A number of studies have shown that heating and chemicaltreatments change the activity of immune cells. Chen (1987) found thatheating murine macrophages to 41° C. to 43° C. for one hour caused themto synthesize and release prostaglandins of the E type. Fouqueray (1992)found that a 20-minute exposure of rat peritoneal macrophages to 39° C.to 41° C. decreased synthesis of tumor necrosis factor alpha andinterleukin-1 within two hours, but monocytes circulating in the bloodwere less sensitive to heating than were the tissue macrophages. Ribeiro(1996) confirmed that heat exposure decreases macrophage release of TNFalpha both in vitro and in vivo. Kunkel (1986) showed that indomethacininhibited lipopolysaccharide (LPS) induced synthesis of prostaglandinsby macrophages (and inhibited heat-induced PGEs (Chen, 1987) butenhanced macrophage production of TNF-I in response to LPS. Morange M.(1986) found that HSPs were induced at lower temperatures when cellswere exposed to interferonalpha and interferon-beta. Ensor (1995)reported that exposing a macrophage cell line to 40° C. for 30 minutesprevented (within six hours) synthesis and release of TNF-I in responseexposure to LPS. The half-life of TNF-I mRNA was shortened. There was nochange in the levels of mRNA for GAPDH, ∂-actin or IL-6. HSP-72 wasincreased at 43° C. The same authors previously showed that in humanmacrophages TNF expression was suppressed at 38.5° C., but HSP-72 wasincreased only above 40° C. Papadimitriou showed that macrophageapoptosis was minimal at 39° C. but substantial at 41° C.

[0021] Although the cellular phenomenon of apoptosis has been studied insome detail in tissue culture, no studies have been directed towarddeveloping that technique for the treatment of inflammation. New methodsare needed for treating inflamed body tissues and in particular to thetreatment of atherosclerotic plaques to prevent rupture. Such methodsshould not induce an inflammatory response and should be capable ofeliminating or neutralizing macrophages or other inflammatory cellswithout damaging blood vessel walls. Novel methods for selectivelyinducing apoptosis are also needed. Such methods will be useful inpreventing the rupture of atherosclerotic plaques and therefore reducethe risk of death from myocardial infarction or stroke.

[0022] Stents

[0023] An intravascular stent is typically an expandable stainless steelwire mesh cylinder that is transported in compressed form into the lumenof a vessel by means of a catheter. Once the desired site is reached,the stent is deployed so that it presses against the vessel wall tomechanically hold the lumen open. Aside from metals and memory metalalloys, plastics have also been used to form stents. Over the lastdecade, cardiovascular stent implantation has become a preferred mode oftreatment following angioplasty and atherectomy procedures, and is nowwidely used in interventional centers throughout the United States andother countries. While various stent devices have almost always improvedshort-term results in vessel patency, at the present time it is not yetdetermined whether any of the many stent designs and materials havesignificant advantages over the others. For example, some stentspenetrate the plaque, whereby a gruel-like material is extruded throughthe strut lattice, provoking an intense thrombotic and inflammatoryresponse. Other stent designs merely compress the plaque mass with lessdisruption of the plaque core. The long-term outcomes with presentlyavailable stents, particularly their ability to inhibit restenosis atthe site of implantation, are still to be determined. (See Topol et al.1998; Oesterle et al. 1998) Particular problems that have beenassociated with stents include thrombus formation and cellularovergrowth. During stent placement the blood vessel wall can bedisturbed or injured, and thrombosis often results at the injured site,causing stenosis (narrowing) or complete blockage of the vessel. Thebasic principle that extensive medial injury leads to more inflammationis common to all coronary interventions. Rupture of a necrotic core,with exposure of the plaque contents, appears to be a potent stimulusfor inflammation and profuse proliferation of smooth muscle cells(Oesterle et al., 1998).

[0024] Stents that remain in place in a patient for an extended periodof time also provide a setting for thrombus formation and for overgrowthof vascular smooth muscle cells on the device itself, which contributesfurther to stenosis, sometimes referred to as “in-stent restenosis.” Forexample, P. W. Serruys has shown (in the “Handbook of Coronary Stents”Martin Dunitz Ltd., London 1997, in FIG. 1.3 on p. 2) by an electronmicroscope scan of a wall stent at three days post-implantation thatdeposits of leukocytes, platelets and thrombus adhere to the wire mesh,and that there is some protrusion of the vessel wall into the lumen.These deposits are thrombotic and mitotic, eventually causing neointimalproliferation and thombotic regions. As a result, the patient is placedat risk of a variety of complications, including heart attack, pulmonaryembolism, and stroke, depending on the placement of the stent.

[0025] In addition to the plaque extruding tendency of lattice-likestent designs, the metal composition and other characteristics of thestent surface are also believed to be important factors for theperformance of an implanted stent. It is well established that stainlesssteel implants such as pacemakers tend to release chromium and nickelions, which can destroy or damage certain enzymes and proteins and canexacerbate allergies to these metals.

[0026] Non-metallic stents have also been used for endovascular support.These devices are generally cylindrical structures made up of a sheet orsleeve of resilient, elastic material which can be cured or hardenedfollowing delivery of the stent to a selected region of a vessel. Forexample, U.S. Pat. No. 5,100,429 (Sinofsky) discloses an endovascularstent having a tubular body formed as a rolled sheet of a biologicallycompatible material having a cross-linkable adhesive material betweenoverlapping portions of the rolled sheet. U.S. Pat. No. 5,591,199(Porter) is for a vascular stent made up of a biocompatible fibrousmaterial that is coated or filled with a curable material so that thefiber composite can be shaped and cured to maintain the shape. U.S. Pat.No. 5,282,848 (Schmitt et al.) discloses a self-supporting stent havinga continuous uniform surface made up of a woven synthetic material. U.S.Pat. No. 5,814,063 (Freitag) describes a method of embedding thesupporting metal stent structure in a cylindrical elastomeric casingsuch as silicone. However, a potential problem with the sleeve or sheettype of stent is that blood may not adequately circulate to the vesselwall adjacent the stent. Fully covering the endothelium of the vesselwall is also undesirable as the endothelium plays an essential role inbiologic activity of the coronary artery, such as fibrinolysis andvasodilation.

[0027] Application of a biocompatible coating to a metal stent iscurrently the most widely-used technique for avoiding problemsencountered with bare metal stents. For example, the DIAMONDT stentproduced by the Phytis Company of Hamburg, Germany has been shown toavoid these metal diffusion problems. Smooth coatings can significantlyreduce the surface roughness of the bare metal surface to improvehydrodynamic behavior and to deter adsorption of proteins, which leadsto thrombus formation. The phosphorylcholine-coated stent manufacturedby Biocompatibles Ltd., Farnham, Surrey, UK, is an example of a morehemocompatible metal-based stent.

[0028] Stent-coating materials that have been used to decrease theinherent thrombogenicity of stents and/or reducing in-stent restenosisinclude the following synthetic substances: polyurethane, segmentedpolyurethaneurea/heparin, poly-L-lactic acid, cellulose ester,polyethylene glycol and polyphosphate ester. Thrombus inhibitors andother therapeutic agents have also been incorporated into the fibermatrix of non-metallic stents, or attached to a biocompatible coatingthat encapsulates a stent. Some of the naturally occurring substancesthat have been described as biocompatible or therapeutic coatings forstents include: collagen/laminin, heparin, fibrin, phosphorylcholine,AZ1 (monoclonal antibody directed against rabbit platelet integrinα_(IIIb)β₃) absorbed to cellulose, and AZ1/UK (monoclonal antibodydirected against rabbit platelet integrin α_(IIIb)β₃/urokinaseconjugate) adsorbed to cellulose. (Topol et al., 1998)

[0029] U.S. Pat. No. 5,749,915 (Slepian) describes a method of forming abiocompatible polymer coating on a vessel wall by providing abiocompatible polymeric material that is non-fluent at body temperature,yet which becomes fluent at an elevated temperature. The material isheated to render it fluent, contacted with a tissue surface to be“paved”, and allowed to cool, thereby providing a non-fluentbiocompatible polymeric covering on the vessel wall.

[0030] Therapeutic stents have also been described as vehicles forprolonged local drug administration, as means for delivery of genetherapy to cells of the arterial wall, and as carriers of viableendothelial cells to passivate the stent surface (See Topol et at.,1998). U.S. Pat. No. 5,674,192 (Sahatjian, et al.) describes adrug-carrying balloon catheter and stent with a polymer coating such asa swellable hydrogel incorporating the drug. The expandable portion ofthe catheter can be adapted for application of heat to the polymermaterial to control the rate of administration. The polymer is meltableand the release of the polymer is aided by the application of heat.

[0031] U.S. Pat. No. 5,906,636 (Casscells, et al.) discloses use of anendolumenal stent to gently heat an inflamed atherosclerotic plaque forreducing inflammation and/or inducing apoptosis in plaque cells as ameans for preventing or delaying restenosis after angioplasty orstenting.

[0032] The use of electromagnetic energy, including microwave, radiofrequency (RF), coherent (laser), ultraviolet (UV) and visible-spectrumlight energy, have been used in various angioplasty and atherectomydevices, endeavoring to destroy plaque without harming the vessel wall.For example, U.S. Pat. No. 5,057,106 (Kasevich) discloses the use ofmicrowave energy for heating atherosclerotic plaque in the arterial wallin combination with dilation angioplasty. U.S. Pat. Nos. 4,807,620(Strul) and 5,087,256 (Taylor) provide representative examples ofatherectomy or angioplasty devices that convert electromagnetic RFenergy to thermal energy. U.S. Pat. No. 5,053,033 (Clarke) describes theuse of an UV laser to inhibit restenosis by irradiation of smooth musclecells with non-ablative cytotoxic light energy. U.S. Pat. Nos. 4,997,431(Isner); 5,106,386 (Isner); 5,026,367 (Leckrone); 5,109,859 (Jenkins);and 4,846,171 (Kauphusman) each disclose the use of laser lighttransmitted via an optical fiber or conduit to reduce tissue mass orremove arterial plaque by ablation. U.S. Pat. Nos. 4,878,492 (Sinofsky)and 4,779,479 (Spears) describe the use of nonablative laser lightenergy of sufficient wattage to heat the arterial plaque during aconventional PTCA dilation procedure in order to fuse fragmented plaqueand coagulate trapped blood. Typically, these kinds of devices fail todistinguish normal vessel wall from atherosclerotic plaque, however.

[0033] Stent-type devices have also been employed for thermal therapy ofvarious annular organs and vessels, almost all of which are directed atinhibiting or killing cancer cells and typically generate temperaturesin the cell necrosing range and beyond. Goldberg (1997) has describedone type of heating stent for applying RF energy to indwelling metallicstents to induce transluminal coagulative necrosis. Another type ofheating stent is disclosed in Japanese Pat. No. 6063154 (Koji et al.),which describes a heat generating stent for placement in an annularorgan for tumor treatment. The hollow stent is made of a thermosensitivemagnetic material that is heated by an external high-energy, alternatingmagnetic field. Similarly, Japanese Pat. No. 6063155 (Koji et al.)describes the application of a thermosensitive medicine-containingpolymer to the thermosensitive magnetic stent to providetemperature-controlled treatment of an annular organ or vessel.

[0034] However, problems may arise when the body is exposed to a highelectromagnetic field. For instance, other implanted metallic objects inthe body, such as pacemakers, defibrillators or cardiovascular stents,may malfunction or heat up dangerously if exposed to a strongelectromagnetic field. Additionally, the effects of high magnetic fieldson biological tissue are still not completely understood. Such fieldsmay cause ionization of some biomolecules and cellular damage. Anotherdisadvantage of techniques requiring high-energy magnetic fieldproduction is that they require facilities that are costly to maintainand are not widely available to the medical community.

[0035] Other methods of heating vessels or other annular organs, such asresistive heating of a fluid-filled balloon catheter, for example, whichrequire passage of electricity to the body are inherently difficult tocontrol and can also present a hazard to the patient. Moreover, all ofthe conventional intravascular heating methods are invasive andcatheter-based.

[0036] Ultrasound (US) is another energy source that is applied to thebody and is particularly well known for its diagnostic imaging utility,particularly in monitoring fetal development and for echocardiography inthe diagnosis of cardiac conditions. Ultrasound is generally consideredto be a safe diagnostic and therapeutic tool when employed clinically,and the beneficial therapeutic effects—both thermal and non-thermal—ofultrasound in physical therapy are widely recognized, particularly forwound healing and in reducing pain. (See, for example, McDiarnid, et al.1987). Therapeutic use of ultrasound for cardiovascular-relatedconditions include, for example, enhancement of thrombolysis bytranscutaneous ultrasound treatment, as described by Luo et al. (1998).Intravascular ultrasound (IVUS) imaging is currently being used toassist stent implantation (Oesterle, 1998). U.S. Pat. No. 5,836,896(Rosenschein) describes a method of inhibiting restenosis by applyingintravascular ultrasonic energy to smooth muscle cells of the vesselwall in order to inhibit the migration and adherence of smooth musclecells. This method, however, takes advantage of the non-thermal effectof ultrasound to produce cavitation within a vessel in a region ofangioplasty or atherectomy injury.

[0037] Diagnostic and therapeutic uses of ultrasound are based on thefact that almost every substance has a characteristic acousticimpedance, which is based on the speed at which ultrasound waves travelin that substance, or medium. Ultrasound waves may move, or propagate,through a medium more or less freely, or they can be absorbed, reflectedor scattered by the molecules of the medium. It is the relativecontribution of each of these factors that determines the speed at whichultrasound will travel in a given medium. Resistance to movement due toabsorbance, reflectance or scattering is generally termed “acousticimpedance.”The acoustic impedance of a substance is equal to the productof the density of the substance and the speed of sound therein.

[0038] Accordingly, each tissue in the body will absorb a certainpercentage of the energy from ultrasound waves that propagate throughit. Ultrasound travels at a speed of about 1.5×10⁵ cm/s in most softtissues. When an ultrasound wave is absorbed, or partly absorbed bytissue, the associated kinetic energy is converted to thermal or heatenergy, raising the temperature of the tissue a corresponding amount. Atthe interface between two acoustically different tissues, such as boneand soft tissue in the body, even more heat is generated by theultrasound due to reflectance by the denser medium. Reflectance canproduce “standing waves,” as discussed by Roy Williams (1987). Recenttests of the effects of ultrasound irradiation on non-living porcinetissue, when placed on both metal and plastic surfaces, were performedby Robertson et al. (1995). The results of those studies showed amarkedly higher maximum temperature increase in the tissue, and asignificantly greater initial rate of heating, when the tissue was onthe metal surface rather than on the plastic surface. Ultrasound,particularly pulsed high intensity ultrasound, can quickly causeexcessive heating and even burning of soft tissue in contact with boneor another acoustically reflective object, such as a conventional metalstent, unless the conditions are carefully controlled.

[0039] Even though ultrasound has been in use both diagnostically andtherapeutically for over a decade, and its beneficial results have beenattributed to both thermal and non-thermal effects, there has beenlittle research on the effect of treatment dosage on the extent oftissue heating. (See, for example, Kimura et al. 1998). Barnett et al.(1994) have reported that exposure to even diagnostic levels of lowintensity ultrasound produce significant temperature increases in vivo,specifically at interfaces between bone and soft tissue. Fan and Hynynen(1992) have reported the effect of wave reflection and refraction atsoft tissue interfaces during ultrasound hyperthermia treatments. Atemperature increase of more than 5° C. has been reported withdiagnostic ultrasound equipment, using either pulsed-wave orcontinuous-wave low intensity ultrasound for tissue close to bone S.Barnett (1998). Wells (1992)) focuses on the biological effects due toheating by diagnostic ultrasound, with particular reference to themonitoring of prenatal development of animals.

[0040] Today, ultrasound thermal therapy is only used for heat deliveryto large volumes of tissue, such as tumors, to burn sites of internalbleeding to achieve coagulation and clot formation, and for physicaltherapy. High intensity focused ultrasound is effective for heatingcancerous tissue, typically increasing the temperature of the targettissue by about 10-20° C. and often up to about 85° C. High intensityultrasound is also used to stop bleeding, in lithotripsy procedures, andfor deep surgery. For example, the SONABLATE™ acoustic ablation device(Focus Surgery, Inc., Indianapolis, Ind.) is reported to permitbloodless noninvasive surgery in all parts of the body. Generally, intissues where heat removal by blood flow or by conduction issignificant, higher energy pulsed beams of focused ultrasound aresometimes employed in order to more quickly achieve the desired level ofheating at a target site. Thermal therapy devices have particulardifficulty in establishing and maintaining the desired therapeutictemperature in highly perfused tissues. Also, blood flowing through anartery makes it very difficult to heat a region of the vessel to adesired temperature. Oftentimes, considerable damage to interveningtissue also occurs as a consequence of the higher energy ultrasoundrequired with existing ultrasound thermal treatment methods.

[0041] Conventional metal stents, when exposed to a focused highintensity ultrasound beam may cause damage or burning of the surroundingcardiovascular tissue due to reflectance by the metallic surface of thestent. It would be desirable to have safer stents that could avoid atleast some of the problems typically encountered with conventionalstents, as described above. A non-invasive way to apply thermal therapyintravascularly would be particularly advantageous over the existingcatheter-based techniques. It would be even more desirable to have a wayto utilize existing ultrasound technology to achieve controlled heatingof stents for particular therapeutic or diagnostic applications, whileavoiding inadvertent or excessive heating and damage to intervening ornon-targeted body tissue.

SUMMARY OF THE INVENTION

[0042] The present invention provides methods that can be used to treatinflammation in body tissues and in particular to treat inflamedatherosclerotic plaques. The methods can be used to decrease oreliminate inflammation in a plaque to prevent rupture. Certain disclosedmethods are particularly useful for inducing apoptosis in localized cellclusters such as the macrophages that cause an inflammatory response.

[0043] The present methods utilize localized and mild hyperthermictreatments to neutralize or preferably to induce apoptosis ininflammatory cells. Localized heat treatments avoid systemic cell damageand at the same time lead to clearance of unwanted cells without causinga secondary inflammation.

[0044] The techniques disclosed herein are useful in the treatment ofinflammation. The term inflammation includes inflamed atheroscleroticplaques; restenosis; and arteritis such as that found in systemic lupus,Takayasu's arteritis, Beheet's syndrome, temporal (gran+ cell)arteritis, myocarditis of the autoimmune etiology; arteriovenousfistulea, dialysis grafts or other vascular prosthesis. The phrase“treating inflammation” also includes treating a region of a vein priorto or after balloon angioplasty, rotational or directional atherectomy,stenting or related interventions that could result in inflammation andsubsequent thrombosis, acute closure or restenosis. Use of the disclosedmethods on atherosclerotic plaques will reduce the chance of myocardialinfarction or stroke.

[0045] Certain methods of the present invention are useful for inducingapoptosis in inflammatory cells. Inflammatory cells primarily consist ofmacrophages and other closely related cells of the immune system thatare involved in creating inflammation. The present methods specificallycontemplate inducing apoptosis in these cells with hyperthermictreatments.

[0046] Some of the present methods are directed to treating inflamedregions containing deleterious immune cells with heat in the range of38.5° C.-44° C. for between about 5 minutes to 60 minutes and moretypically for at least about 15 to 30 minutes. At the high end of thetemperature range, from about 41° C. to 44° C., apoptosis is moreeffectively induced. Temperatures above 44° C. are not preferred becausethey begin to cause cell killing through necrosis and pathways thatcause secondary inflammation. Treatments at the low end of thetemperature range may also be effective. For example, heating withtemperatures in the range of 38.5° C. to 40° C., which are below thosenecessary to cause apoptosis on brief exposures (e.g., 15 minutes) canbe used to decrease macrophage production and their release ofcytokines. These temperatures are contemplated to be within the presentinvention. Generally, temperatures of approximately 42° C. to 43° C.will be used.

[0047] In patients, following routine angiography, a heat detectingprobe, such as is described in U.S. patent application Ser. No.08/717,449, would be used to identify lesions that are significantlyhotter than the rest of the artery. Lesions at higher risk of ruptureare about two degrees warmer than adjacent tissue. These lesions aredetectable by heat imaging catheters consisting of any of several fibersthat conduct heat, bundled into a standard coronary or otherangiographic catheter ranging from 4 French to 14 French in diameter.Alternatively, a catheter with standard heat sensing electrodes on itssurface could be used. In one embodiment, this would be a ballooncatheter made of a compliant (soft) balloon material, so as not todamage the endothelium or disrupt the plaque itself.

[0048] Heat may be transferred to the target cells by a variety ofmethods. For example, heat may be transferred into an inflamed plaque ina blood vessel by means of a catheter. Several catheters arecommercially available that are capable of introducing the heat requiredfor these techniques. In addition, the catheter disclosed in U.S. patentapplication Ser. No. 08/717,449 can easily be equipped to emit infraredradiation by one of skill in the catheter arts. Preferred catheters arethose that can deliver heat within the temperature range of 38.5-44° C.Catheters that emit heat above about 45° C. are not preferred becausethe use of such elevated temperatures may damage endothelial cells andproduce a secondary inflammatory response.

[0049] Preferred embodiments of the present invention introduce heatinto a region of inflamed tissue by introducing a stent into the lumenof a blood vessel or the lumen of an organ to treat inflammation inblood vessels, parenchymal smooth muscle cells or interstitial cellssuch as fibroblasts to prevent obstruction and/or thrombosis in thelumen. Methods for positioning stents are well known in the art. Thestent is positioned in such a way as to be in thermal contact with aregion of inflamed tissue. The stent is then heated. It can be heatedelectrically or with microwave or radio frequency radiation or othermeans. These heating methods can be produced from devices such ascatheters within the lumen or from energy sources such as radiofrequencysources outside the body. It would be clear to one of skill in the artthat the stent used in such an application must be able to transmitheat. The preferred stents are made of metal.

[0050] Although the present techniques primarily rely upon heatingmethods, chemical agents or radiation may also be employed to augmentthe effectiveness of heat treatments. For example, beta-blocking drugs,cytokines such as insulin-like growth factor, transforming growth factorB1, vascular endothelial growth factor, fibroblast growth factor, tumornecrosis factor and the like may be used to enhance the susceptibilityof macrophages to heat induced apoptosis or to increase the resistanceof endothelial cells to apoptosis. Effective amounts of these drugs caneasily be determined by one of skill in the art.

[0051] Preferred embodiments of the present invention includeultrasonically heatable stents containing biocompatible material thatheats more rapidly than does human soft tissue when a focused beam ofultrasound is directed onto the implanted stent. The disclosed methodsof the invention provide a new way to invasively or non-invasively heata tissue which is in contact with one of the coated stents of theinvention by directing ultrasound at the implanted stent. TheUS-heatable stents of the invention also avoid at least some of theproblems encountered by other US thermal therapy devices in establishingand maintaining the desired therapeutic temperature in a target tissue,particularly when one is hampered by the presence of blood perfusion inthe tissue. Blood flowing through an artery makes it very difficult toheat a region of artery wall to a desired temperature. Theultrasound-absorptive coated stents of the disclosed invention achievecontrolled heating for particular therapeutic or diagnosticapplications, while avoiding the inadvertent or excessive heating anddamage to non-targeted body tissue commonly encountered with otherheating stents. The stents of the present invention, and their methodsof use, advantageously employ the acoustic impedance properties oftissues and of various biocompatible polymers, among other things. Also,the “double heating” effect that occurs due to reflectance of ultrasoundby metal and at dissimilar acoustic interfaces are employed to achievesite-specific therapeutic heating of targeted regions of vessel wall.

[0052] As described in more detail below, ultrasonically heatable stentsare provided which, after initial endolumenal placement, can be eitherinvasively or non-invasively warmed to produce therapeutic levels ofheat in the stent. Similarly, exemplary methods are also described forheating in situ a synthetic vascular graft.

[0053] In accordance with the present invention, an ultrasonicallyheatable stent is provided. The stent may be configured, or designed tomaintain the patency of a human vessel, such as a coronary artery, forexample. The stent contains an ultrasound-absorptive material thatpossesses a characteristic acoustic impedance value that is greater thanthat of living tissue. For the purposes of this disclosure an“ultrasound-absorptive material” is defined as one that absorbs anappreciable amount of the energy of an ultrasound beam whereby thetemperature of the material increases. The ultrasound-absorptivematerial may be used to form the entire structure of the stent.Alternatively, the basic structure or framework of the stent may be madeof another material, such as wire mesh, which provides the main supportfunction of the stent and is configured to maintain patency of thevessel. In the latter embodiment, a coating of the ultrasound-absorptivematerial covers or overlies the stent framework and is characterized bybeing heatable by ultrasound at a faster rate than living soft tissue.For example, the stent coating may contain at least one US-absorptivematerial that has a heating rate greater than 0.86° C. per minute whensubjected to an ultrasound beam of 1 mHz frequency and 1 Watt/cm²intensity.

[0054] Certain embodiments of the stent include a polymer that has atleast one of the US-absorptive coating materials. Examples of some ofthe synthetic polymers that may be used are silicone, polyvinylchloride,nylon and polyurethane. Combinations of these materials may also be usedin order to optimize the heating rate of the coating or to improvestability or biocompatibility of the coating. In some embodiments, thecoating also includes a heat-releasable drug for local release at thesite of the stent.

[0055] In an alternative embodiment of the stent of the presentinvention, the US-absorptive coat contains at least two layers ofUS-absorptive material. One of the layers covers at least one otherlayer, which is sandwiched between the framework and the outer layer.These two or more layers have dissimilar acoustic impedancecharacteristics. These two layers and their distinct interfaces worktogether to enhance the ultrasound-induced temperature increase of thecoat when exposed to ultrasound. For example, the coating preferably hasthe characteristic that its temperature will increase 1-5° C. or more inresponse to ultrasound irradiation at a chosen wave frequency, intensityand duration. The coating will preferably also have the characteristicthat its acoustic impedance is greater than that of any interveningtissue located between the stent and an external ultrasound transducer,when said stent is situated in a vessel and ultrasonic radiation isdirected toward said stent. This feature prevents tissue in the path ofthe ultrasonic beam from being damaged or excessively heated before thestent reaches the desired temperature.

[0056] Also provided by the present invention is a method of making thenew ultrasonically heatable stents. The method includes obtaining astent framework configured for maintaining patency of a vessel, andobtaining a biocompatible coating material characterized by having anacoustic impedance greater than that of living tissue. The coatingmaterial is applied to the stent framework in such a way that the finalthickness and character of the coating permits the stent to be heatableby ultrasound at a faster rate than living tissue, as described above.

[0057] Also in accordance with the present invention, a method of makingan ultrasonically heatable stent is provided. One exemplary stent ismade by modifying a basic metal stent framework configured formaintaining patency of a vessel, such as a commercially available wiremesh, or zigzag stent. Over the stent framework is applied a coat orlayer of a biocompatible coating material that is characterized byhaving an acoustic impedance greater than that of living tissue, such asthat in the human body. The thickness and other characteristics of thecoating are such that said the stent is heatable by ultrasound at afaster rate than living tissue. For example, a heating rate greater than0.86° C. per minute when subjected to an ultrasound beam of 1 mHzfrequency and 1 Watt/cm² intensity is characteristic of certain coatedstents of the invention. One suitable coating material is silicone, andothers include nylon, polyvinylchloride, polyurethane andphosphorylcholine, for example. Combinations of coating materials mayalso be used. The coating may also be applied in layers of the same ordifferent ultrasoundabsorptive material, so as to form additionalacoustic interfaces. The thickness and manner of coating the stent canbe varied such that the resulting coated stent is heatable by ultrasoundat a faster rate than the surrounding living tissue. For example, atemperature about 1-5° C. above ambient temperature is generated in thestent.

[0058] The present invention also provides a method of treating anatherosclerotic plaque in a living subject. An ultrasonically heatablestent, as described above, is positioned in a vessel lumen in such a waythat it contacts a region of vessel wall where an atherosclerotic plaqueis located. One particular kind of site in need of treatment is astenotic plaque that has recently undergone an angioplasty oratherectomy procedure. An ultrasound transducer is advantageouslypositioned outside of the body of the subject, and operated to cause anultrasonic beam to be directed onto the stent inside the vessel. For thepurposes of this disclosure, the term “advantageously positioned” meansthat the transducer is located as optimally as possible or practical fordirecting ultrasound waves toward a particular target. For example, onewould try to avoid having hard or interfering surfaces between thetransducer and the internal target. Also, positioning the transducerclose to the target reduces the depth of penetration of the ultrasoundwaves required in order to reach the target stent. Due to the choice ofultrasonically heatable coating material covering the stent, and theoptimal operation of the ultrasound system, the temperature of the stentis warmed to and maintained at about 1-5° C. above the ambienttemperature of the vessel. The ultrasonic heating of the stent iscontinued while the region of vessel wall contacted by the stent isheated at 38-42° C. for a sufficient period of time to achieve thedesired therapeutic goal, such as reducing post-injury inflammation orinhibiting cellular proliferation.

[0059] To further optimize the procedure, the temperature of the stentand/or the heated area of vessel wall is measured, using a conventionalremote temperature monitoring method. Also, the ultrasound irradiatingand temperature measuring steps can be repeated at the desired timeintervals, as considered by the user to be medically beneficial.Optionally, but preferably, a microprocessor and visual display systemis employed to control the operation of the ultrasound transducer and toreceive, analyze and display the temperature measurements. It is alsopreferred in some embodiments that the ultrasonic transducer operate inthe frequency and intensity ranges employed with conventional physicaltherapy equipment, for example, about 1-3 mHz frequency and 0.8-1.5Watts/cm² intensity for a sufficient time to heat and hold the stent atthe desired temperature. In some embodiments, at least two transducersare arranged in an array around the body of the patient and eachtransducer is operated in cooperation with the others so that two ormore ultrasonic beams are directed at the stent from differentdirections. The depth of penetration of the ultrasound signal and theamount of heating obtained with a particular stent is adjusted by tuningthe frequency of the ultrasound signals. Also, the width of the beam canbe narrowed by conventional means, for example an acoustic lens can beemployed to focus on a desired spot, if desired. By choosing a suitableultrasound heatable material and by advantageously positioning thetransducers and adjusting and focusing the ultrasound appropriately, thetemperature of the stent is more easily or quickly warmed up to and heldin the desired temperature range. For example, the ultrasound heatingsystem is adjusted so that the stent is maintained at about 1-5° C.above ambient vessel temperature for the length of time that is neededto heat the area of vessel wall surrounding the stent at 38-42° C.

[0060] In one embodiment of the present invention, a method of treatinga site on a vessel wall includes placing an ultrasound transducer insidethe esophagus, similar to the transducer placement for conventionaltrans-esophageal echocardiography. In some embodiments of the method oftreating atherosclerotic plaque, an intravascular ultrasound transduceris positioned inside the stent instead of positioning one or moretransducers outside the body. This is particularly desirable if anotherintravascular procedure is being performed on the patient, and the twoprocedures can be combined.

[0061] A method of treating a vascular injury, such as an angioplasty oratherectomy site, for inhibiting restenosis is also provided by thepresent invention. Similar to the method of treating an atheroscleroticplaque, an ultrasonically heatable stent is positioned along the vesselwall at a site where an angioplasty or atherectomy procedure has beenrecently performed. The site is subjected first to ultrasound-inducedheating at 39-40° C. to reduce post-injury inflammation. This 39-40° C.heating can be repeated in a periodic manner in order to remove anyresidual or recurring inflammatory deposits on the surface of the stent,as deemed medically necessary. Subsequently, especially if restrictedblood flow through said stent is detected, an ultrasound transducer mayagain be applied such that an ultrasonic beam is directed onto thestent. In the second phase of treatment, the stent is maintained at atemperature about 1-5° C. above ambient vessel temperature long enoughto heat any vascular tissue overgrowth and accumulated inflammatorycells to induce apoptosis. For example, the second phase heating couldbe 42° C. for at least 15 minutes, to induce apoptosis in smooth musclecells and in macrophages. If desired, the accuracy and ease ofperforming the procedure can be facilitated by non-invasively monitoringthe temperature of the stent or the region of vessel wall. Also, amicroprocessor and visual display can be used to receive, analyze anddisplay the temperature measurements.

[0062] Another method encompassed by the present invention includes amethod of reducing or eliminating a population of inflammatory cells onan implanted synthetic vascular graft, such as an arterio-venous (AV)graft, in a living subject. According to this method, an ultrasoundtransducer is advantageously positioned with respect to the location ofthe stent and is operated in such a way that an ultrasonic beam isdirected on the graft. In this way the temperature of the graft, or aportion thereof, is increased about 1-5° C. above the ambient vesseltemperature. This temperature elevation is maintained for a sufficientperiod of time to heat the graft, or portion thereof, at a temperatureof 38-42° C. As described before, a microprocessor and monitor may beincorporated in the treatment system and ultrasound operation andtemperature measurement steps may be repeated at therapeuticallybeneficial intervals.

[0063] Still another embodiment of the present invention provides amethod of inhibiting or regressing in-stent restenosis. After anultrasonically heatable stent of the invention is implanted into thevessel of a subject, vascular and inflammatory cells may invade orover-grow the stent, as sometimes occurs with mesh-type stents. In thiscase, however, an ultrasound transducer is positioned outside of thebody and a low-intensity ultrasonic beam is directed at the stent. Theultrasound beam is operated in such a way that the temperature of thestent is increased to about 1-5° C. above the ambient vessel temperaturefor a sufficient period of time to heat the stent at a temperature ofabout 42° C. Optionally, ultrasound irradiation and temperaturemeasurement steps are repeated at therapeutically beneficial timeintervals. For example, it is desirable to heat up the stent when bloodflow through the stent has become restricted, when overgrowth ofvascular smooth muscle cells into the stent is believed to haveoccurred, or to reduce the size of blood clots in or around the stent.This procedure may also employ a microprocessor and visual displaysystem to control the operation of said ultrasound transducer and toreceive, analyze and display said temperature measurements, wherebyapoptosis is induced in a population of cells of the overgrown tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

[0064]FIG. 1 is a graph showing the percent of cells from Watanabe(atherosclerosis) rabbit aorta tissue undergoing apoptosis afterexposure for 15 minutes at the temperatures shown.

[0065]FIG. 2 is a graph showing the percent of cells in apoptosis fromhuman endarterectomy tissue after heating in cell culture for 15 minutesat the temperatures shown.

[0066]FIG. 3 is a graph showing the relationship of heat as measured byan infrared camera, to cell density in living human carotidendarterectomy specimens.

[0067]FIG. 4A is a photomicrograph of a representative specimen of humancarotid endarterectomy tissue heated to 44° C. for 15 minutes.

[0068]FIG. 4B is a photomicrograph of an unheated portion of thespecimen of human carotid endarterectomy tissue shown in FIG. 4A.

[0069]FIG. 5 is a schematic representation of the test set-up fordetermining the ultrasound heating characteristics of a variety of stentmaterials.

[0070]FIG. 6 is a graph showing the ultrasound heating effects (°C./second) of a sample of silicone polymer and a soft-tissue specimensituated between the polymer and an ultrasound transducer operated incontinuous-wave mode at an intensity (power) of 1 Watts/cm².

[0071]FIG. 7 is a graph showing the ultrasound heating effects (°C./second) of a sample of TEFLON™ polymer and a soft-tissue specimensituated between the polymer and an ultrasound transducer operated incontinuous-wave mode at an intensity (power) of 20 Watts/cm².

[0072]FIG. 8 is a graph showing the ultrasound heating effects (°C./second) of a sample of HAEMOFLO™ polyvinylchloride polymer and asoft-tissue specimen situated between the polymer and an ultrasoundtransducer operated in continuous-wave mode at an intensity (power) of20 Watts/cm².

[0073]FIG. 9 is a graph showing the ultrasound heating effects (°C./second) of a sample of NYLON™ polymer and a soft-tissue specimensituated between the polymer and an ultrasound transducer operated incontinuous-wave mode at an intensity (power) of 5 Watts/cm².

[0074]FIG. 10 is a graph showing the ultrasound heating effects (°C./second) of a sample of LEXAN™ polymer and a soft-tissue specimensituated between the polymer and an ultrasound transducer operated incontinuous-wave mode at an intensity (power) of 5 Watts/cm².

[0075]FIG. 11 is a graph showing the ultrasound heating effects (°C./second) due to ultrasound waves reflected from a metal coil stent ona soft-tissue specimen situated between the metal stent and anultrasound transducer operated in continuous-wave mode at an intensity(power) of 5 Watts/cm².

[0076]FIG. 12 is a graph showing the predicted effects of heat onmacrophages in atherosclerotic plaques.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0077] The following examples are offered by way of illustration and arenot intended to limit the invention in any manner. All temperatures arein degrees Celsius unless otherwise noted.

EXAMPLE I

[0078] The inventors have discovered that macrophages are moresusceptible to heat induced apoptosis than endothelial cells. Thisdiscovery led to the development of the present techniques that use heatto reduce inflammation in inflamed tissue and especially in inflamedatherosclerotic plaques. However, greater sensitivity to heat-inducedapoptosis of macrophages is not a requirement of the invention becausemany athersclerotic plaques are denuded of endothelium in which caseinduction of endothelial cell apoptosis would be moot.

[0079]FIG. 1 shows the percent of cells from Watanabe (atherosclerosis)rabbit aorta tissue undergoing apoptosis after exposure for 15 minutesat the temperatures shown, followed by “TUNEL” staining after a 6 hourincubation at 37° C. FIG. 2 shows similar results when the cells inhuman carotid artery endarterectomy samples were investigated in asimilar manner. Living human carotid atherosclerotic plaque was obtainedby endarterectomy, immediately placed in tissue culture and subjected tovarying temperatures for fifteen minutes. After four subsequent hours at37° C. these specimens were fixed and processed for light and electronmicroscopic histology. The sections were subjected to histochemistry forthe enzyme terminal deoxynucelotidyl transferase, which results in ablue color in the apoptotic cell. A kit from Trevigen, Inc(Gaithersburg, Md., 20877) was used with the appropriate positive andnegative controls. As a further control the stained cells were evaluatedby electron microscopy. The results show a significant number ofapoptotic cells at 37° C. There was an increase in the number ofapoptotic cells at 42° C. with a peak at 45° C.

[0080] These results were confirmed by electron microscopic finding ofchromatin margination, protrusions and nuclear fragmentation and buddingwith the production of membrane bound apoptotic bodies. Light microscopysuggested that almost all of the cells undergoing apoptosis weremacrophages. Finally, a minority of endothelial cells underwentapoptosis with 15 minutes of exposure to 45° C., suggesting that thereis indeed a window in which the macrophages can selectively be inducedto undergo apoptosis.

[0081]FIG. 3 shows more directly the relationship between cell densityand heat produced as measured by an infrared camera. The elevated heatproduced in areas having elevated numbers of macrophages facilitates adetection method for identifying inflamed plaques as discussed in U.S.patent application Ser. No. 08/717,449. In FIG. 4 is shown the resultsfrom a study in which a representative specimen of human carotidendarterectomy tissue was divided and half. One half shown in FIG. 4Awas incubated at 44° C. for 15 minutes in a humidified incubator,followed by 6 hours at 37° C. The other half was maintained at bodytemperature. “TUNEL” staining for DNA was employed to demonstrateapoptosis. The cells are indicated by the dark stain. No counterstainwas used in this section. The capillary nuclei are faintly shown asunstained macrophage nuclei. The photograph demonstrates the differencebetween the nuclei of heated and unheated cells.

EXAMPLE II Treatment of Inflamed Plaques

[0082] Typically, heat induced apoptosis of inflammatory cells toprevent rupture and/or thrombosis of atherosclerotic plaques in thecoronary, carotid, iliac femoral or superficial femoral arteries will becarried out in patients presenting with symptoms of ischemia. Forexample, patients with angina or a positive stress test, or patientswith a recent myocardial infarction who are undergoing coronaryangiography, will have an infrared catheter passed down the artery in afashion similar to that of intravascular ultrasound or angioscopy, asdescribed further below.

[0083] Some patients will be referred for this procedure for otherreasons. For example, patients having plasma that shows biochemicalevidence of inflammation or thrombosis, or endothelial damage or silentmyocardial damage, may require coronary catheterization. Alternativetests which might bring non-symptomatic people to coronary angiographyand infrared testing might include a magnetic resonance imaging scanwhich can give a kind of non-invasive thermometry, or positron emissiontomography, which gives a non-invasive image of glucose utilization(this may indicate macrophage presence because of their high glucoseconsumption when activated).

[0084] The patients who come for peripheral angiography have come eitherbecause of claudication or embolism to the feet or because a doctor hasfound diminished pulses on physical examination. Patients requiringcarotid angiography typically have had a stroke or transient ischemicattack or a bruit has been detected on physical examination or a carotidnarrowing has been detected in the course of magnetic resonance imaging,Doppler imaging or angiography performed for other reasons.

[0085] In the patients described above, following routine angiography, aheat detecting probe, such as is described in U.S. patent applicationSer. No. 08/717,449, will be used to identify lesions that aresignificantly hotter than the rest of the artery. Lesions at higher riskof rupture are generally abouttwo degrees warmer than adjacent tissue.These lesions could be detected by an imaging catheter consisting of anyof several fibers that conduct heat, bundled into a standard coronary orother angiographic catheter ranging from four French to seven French indiameter. Alternatively, a catheter with standard electrodes on itssurface could be used. In one method this will be a balloon cathetermade of a compliant (soft) balloon material, so as not to damage theendothelium or disrupt the plaque itself.

[0086] Additional evidence that a particular lesion may pose a high riskto the patient, even though the stenosis may be no more than twenty orthirty percent in cross sectional diameter, may be provided by othertechniques such as intravascular ultrasound (to determine how thin thefibrous cap is), optical coherence tomography which detects cracks inthe plaque surface, and/or angioscopy which detects superficialthrombosis.

[0087] Treatment of an inflamed lesion will be performed in severalways. One method is to gently heat the inflamed tissue with heat fromabout 38.5° C. to approximately 44° C. The treatment is gentle so as notcause cell death due to protein denaturation, desiccation, vesicationand/or necrosis. This heating step will be carried out for approximately15 minutes. This treatment will trigger programmed cell death(apoptosis) in the inflammatory cells and spares endothelial cells. Acatheter equipped to radiate heat will be used in this method by placingthe tip at the location of the “hot” plaque and directing heat into theplaque. Subsequently, thermography can be repeated to determine thesuccess of the treatment.

[0088] Lower amounts of heat will also be used to treat inflamed tissue.For example, heating to 38.5° to 41° (which induces apoptosis in asmaller percentage of macrophages) will have the beneficial effect ofdecreasing inflammation produced by macrophages by reducing theproduction of cytokines such as interleukin 1 and interferon gamma.Likewise heating times can be varied. Thus, it is envisioned that sometreatments will be for approximately 60 minutes, particularly when lowertemperatures will be used. In some cases heating times may be as shortas 5 minutes, especially when higher temperatures will be used.

[0089] Adjunctive treatments will include the use of cytokines that areknown to deactivate macrophages. Examples of cytokines envisioned forthese treatments include TGF-B1 and TNF-I. Other adjunctive therapieswill be those directed to preventing the attachment of cytokines totheir receptors, the attachment of monocytes, lymphocytes or neutrophilsto cells, the expression of selectins or cytokines or chemotacticfactors by endothelial cells, soluble receptors and other antagonists ofinflammatory cytokines and chemotactic factors, as well as chemicaltreatments that destroy inflammatory cells.

[0090] The present invention has been described in terms of particularembodiments found or proposed to comprise preferred modes for thepractice of the invention. It will be appreciated by those of skill inthe art that, in light of the present disclosure, numerous modificationsand changes can be made in the particular embodiments exemplifiedwithout departing from the intended scope of the invention. For example,a catheter equipped with a laser or other heat source can be substitutedfor a catheter that produces infrared radiation. In addition, thistechnique could be adapted to prevent or delay the onset of tissuerejection and treatments of other inflamed tissues, such as restenosisafter balloon angioplasty or related interventions including stentingand rotational or directional atherectomy (since macrophage density inthese tissues predicts restenosis (Moreno) elimination of macrophages byheat-induction of apoptosis will reduce the likelihood that restenosiswill occur). Another application will be stenosis of arteriovenousfistulae, dialysis grafts, and other vascular prostheses. In theseapplications, heat therapy can be applied either from within the vesselor across the skin by means of infrared radiation, radiofrequency,heated metal, etc. Still another application would be the use ofmicrowave or radiofrequency to preferentially heat a metal stent toinduce macrophage apoptosis to prevent stenosis or resterosis. All suchmodifications are intended to be included within the scope of theappended claims.

[0091] The methods and devices of the present invention take advantageof the properties of certain types of plastics, polymers and othercoating materials that make some of them more susceptible to heatingthan others. For example, some plastics melt when heated to a giventemperature, and others do not. The inventors observed that not only doa variety of biocompatible plastics and other conventional coatingmaterials for medical devices differ in their melting temperatures, theyalso differ in the amount of heating they undergo in response toultrasound radiation. In the case of ultrasound, the amount of heatingthat occurs depends upon how large a part of the ultrasound wave isabsorbed by a medium and converted to thermal energy. The presentinvention also takes advantage of the “double heating” effect thatoccurs with ultrasound irradiation due to reflectance of sound waves atdissimilar acoustical interfaces.

[0092] “Double heating” means that not only is a medium heated byabsorbance of a portion of the primary ultrasound waves, but it is alsoheated by absorbance of secondary waves that initially propagatedthrough the medium and are reflected back into the medium. Thisreflectance occurs at the interface between the medium and anothermedium that has a higher acoustic impedance. As discussed in more detailbelow, by directing one or more beams of ultrasound from a transducerpositioned outside the body onto a plastic-covered stent, for example,the temperature of the vessel tissue surrounding the stent can beincreased by about 1-5° C., or more. High reflectance of the metallicstent framework and high US absorbency and good thermal conductionproperties of the coating material all contribute to achieving goodheating of the surrounding tissue for therapeutic purposes.

[0093] Making an Ultrasonically Heatable Therapeutic Stent

[0094] A vascular stent such as the commercially availablePALMAZ-SCHATZ™ stent (Cordis Corporation (a Johnson & Johnson company),Miami Lakes, Fla.) provides the basic stent structure or framework forthe new ultrasonically heatable stent. However, substantially anyconventional cardiovascular wire stent that is configured for placementin a vessel of the body would also serve satisfactorily, dependingprimarily on the user's choice of stent configuration and chemicalcomposition for particular medical applications.

[0095] A uniform coating of silicone is then applied to the entire stentbase by dipping it into melted or liquified silicone, or an organicsolution thereof, and then hardening or drying the silicone to form asmooth coating. Silicone is a preferred coating material, in part, dueto its high acoustic impedence and US heating rate relative to that ofvessel tissue, and due to its excellent biocompatibility and chemicalstability, even under conventional sterilization temperatures. Otherdesirable polymers that provide good ultrasonically heatable coatingsare polyvinylchloride, nylon and polyurethane, and the like. The bestcoating materials are those that are not only good absorbers ofultrasound, but also receive the ultrasound waves reflected by the metalsurface of the stent framework without breaking down. Ideally this“double heating” effect enhances the ability of the coated stent to heatthe adjacent tissue in a controlled manner.

[0096] Several synthetic polymers were tested in vitro to determinetheir ultrasound heating characteristics compared to a non-living tissuespecimen. A schematic representation of the test set-up is shown in FIG.5. A first piece of fresh beef muscle tissue 12, representative of humansoft tissue, was placed between a sample of polymer material 14 and theultrasound transducer 16. A second piece of fresh beef muscle tissue 18was placed below the polymer material 14. The tissue specimens were heldat about 4° C. until commencement of the test, whereupon they wereequilibrated at room temperature. The temperature of tissues 12 and 18and of polymer sample 14 at fixed distances from transducer 16 wasmonitored by way of thermocouples 20, placed as shown in FIG. 5. Theultrasound transducer was operated in continuous-wave mode at anintensity (power) in the range of 1-20 Watts/cm² and at a frequency of 1mHz. The heating rates of the various materials are shown in FIGS. 6-11.FIG. 6 is a graph showing the ultrasound heating effects (° C./second)of a sample of silicone and a soft-tissue specimen situated between thepolymer and the ultrasound transducer. FIGS. 7-10 are similar graphs forTEFLON™, polyvinylchloride (HAEMOFLO™), NYLON™ and LEXAN™, respectively.These data show that LEXAN™ heated at about the same rate as theintervening tissue, while the intervening tissue heated significantlyfaster when the “stent” material was TEFLON™. By contrast, silicone andpolyvinylchloride samples heated much faster than the tissue. Even nylonwas heated by ultrasound at a faster rate than the intervening tissuespecimen.

[0097] The enhanced or double heating effect of ultrasound heating onsoft tissue due to reflectance of ultrasound waves back into the tissuecan be seen from the graph shown in FIG. 11. A metal coil was placedinside a soft-tissue specimen, similar to the polymer test conditionsshown in FIG. 5, with thermocouples located next to the metal coil andinside the tissue. The ultrasound transducer was operated incontinuous-wave mode at an intensity (power) of 5 Watts/cm². It can bereadily seen that the temperature of the tissue between the ultrasoundtransducer and the metal coil increases at about the same rate as themetal coil, at least up to about 300 seconds of continuousultrasonication at 5 Watts/cm². Given that about 90% of an ultrasoundwave is reflected by a metal surface, the temperature of the metal coilin this test should be indicative of the temperature of the adjacenttissue. Comparing the heating rate of tissue using a metal “stent” tothe rate using a silicone “stent,” it can also be seen that after about300 seconds the mass of intervening tissue between the metal coil andthe transducer was about 3° C. hotter than that between the siliconesample and the transducer. This strongly suggests that a silicone coatedstent, for example, can be selectively warmed by ultrasound withoutexcessively warming a mass of intervening tissue, and that the heatedstent can warm a small region of immediately adjacent tissue by thermalconduction.

[0098] For a given coating material, the thicker the coat, the more heatcan be generated by ultrasound irradiation. However, due to differencesin acoustic impedence properties of different coating materials, athinner coat of one polymer may be more desirable than a thicker coat ofanother polymer, for example. In any case, the polymer coat should notbe so thick as to close up the mesh of a wire mesh framework and shouldnot increase the diameter of the finished stent so much that it cannotbe readily maneuvered into place in a vessel. The particular coatingmaterial that is selected, and the thickness and layeringcharacteristics of the coat, will provide an ultrasound-inducedtemperature increase of about 1-5° C. when irradiated with low, mid orhigh intensity ultrasound. The most preferred coating materials arethose which permit heating of the stent by low intensity ultrasound.Such coated stents will permit adjacent tissue to be heated at about38-42° C., by thermal conductance from the coating material. Byoptimizing the choice of coating material and the reflective interfacecharacteristics, and by fine tuning the depth of penetration and theintensity of the ultrasound beam, the temperature of the stent can beraised a few degrees higher than 5° C., if desired.

[0099] As an alternative to using silicone, another biocompatible,chemically stable coating material may be used, provided that it has anacoustic impedence value that is higher than that of the target vesseltissue at the site of placement of the stent. It is essential that thecoating material chosen be able to be heated by ultrasound and toconduct heat to the surrounding tissue at a heating rate that issignificantly greater than the rate at which the tissue is directlyheated by the ultrasound traveling through it. Coatings of choice willnot have the acoustic behavior characteristics of metal (i.e., maximumreflectance and minimum absorbency). Other suitable synthetic polymersthat may be used for the ultrasonically heatable coating includepolyurethane, polyvinylchloride and nylon, for example. An alternativeto applying the coating by dipping or spraying, the polymer coating mayalso be applied by vapor deposition, if appropriate. Examples ofpolymers that are particularly suited to vapor or plasma deposition ontoa metal framework are polyimide, parylene and parylene derivatives. Ifdesired, a mixture of polymers, co-polymers, or other coating materialsmay be used to optimize the impedance characteristics of the coat.Whichever coating material is selected, it should adhere well to themetal stent structure or framework, should be sterilizable, and shouldnot appreciably detract from the flexibility, strength and othercritical features of the basic stent structure. Suitable coatings are atleast somewhat elastic and flexible enough to expand and contract alongwith the underlying stent framework without cracking or splitting, andstable at temperatures up to about 42° C.

[0100] If desired, the coating may also include a drug for release atthe stent implantation site. In this case, the coating material selectedis a US-heatable polymer that releases a portion of the drug upon beingheated to a threshold temperature. Of the various naturally occurringsubstances that have been mentioned as coatings for medical devices,including collagen/laminin, heparin, fibrin, AZ1 (monoclonal antibodydirected against rabbit platelet integrin) α_(IIIb)β₃) absorbed tocellulose, and AZ1/UK (monoclonal antibody directed against rabbitplatelet integrin α_(IIIb)β₃/urokinase conjugate) adsorbed to cellulose,some may also be of use in making an ultrasound heatable stent,particularly in combination with a more ultrasound-absorptive material.Inclusion of these types of coating materials may be useful inapplications where particular vascular therapeutic effects are desired.An alternative temperature sensitive drug-releasing stent comprises abiodegradable stent material which, after several gentle heatingrepetitions, becomes completely absorbed or dissolved in the tissue, forexample, after about 6 months to a year. Such a stent would providetemperature controlled stent degradation along with timed drug release.

[0101] To take further advantage of ultrasound wave reflectance thatoccurs at interfaces, for the purpose of enhancing the heatingproperties of the stent, some coating materials may be advantageouslyapplied in discontinuous layers. One way this can be accomplished byapplying multiple thin layers of the same coating material. If desired,one or more different layers of coating material may be applied over theinitial coat. This is especially advantageous if additional “doubleheating” effects are needed to produce a higher temperature in thecoating of the therapeutic stent, for example, more than about 1-5° C.above ambient. By choosing a first coating material (inner layer) havinga higher acoustic impedence than the second (outer) coating, a certainamount of reflectance at the interface of the two dissimilar coatingmaterials can be expected. This is in addition to the reflectance thatoccurs at the metal/first coating interface and that increases theheating of the inner layer. Another advantage of applying an outer layeris that it could also serve to insulate the body from a lesswell-tolerated polymer used for the inner coating. For example, ahemocompatible and phosphorylcholine outer coating may be applied over arapidly heating polymer to provide the advantage of hemocompatability orresistance to clot formation.

[0102] Since the tissue around the new stent is warmed primarily byconduction of heat away from the coated stent, the choice of materialused for each layer should also take into consideration the relativethermal conductance properties of a material. For many applications itis desirable to limit the thermal conduction through the metal frameworkand into the circulating blood. Therefore, a coating material with lowerthermal conductive properties is preferred on the inside (lumen) of thestent. Since there are suitable materials that absorb more US energy andothers that absorb less, a multi-layer coating can be constructed whichpermits heating of the outside of the stent while isolating the heatfrom the interior of the stent to prevent overheating of the blood. Forsome uses, however, such as when in-stent stenosis occurs, it isdesirable to heat both sides of the stent. As discussed in more detailbelow, when the stent is covered with proliferated smooth muscle cellsand infiltrated inflammatory cells it is necessary to heat the internalpart of the stent in particular.

[0103] As an alternative to applying one or more ultrasonically heatablecoatings to a metal framework, a satisfactory ultrasonically heatablestent can also be made by forming the entire device, including theframework, out of a suitable biocompatible material. Suitable materialsare those that have an acoustic impedance that is greater than that ofthe vessel tissue. For example, a stent may be molded of a polymer suchas silicone. Another biocompatible polymer with suitable acousticimpedence characteristics could also be employed, provided that thestent structure is of sufficient strength to hold open a section ofvessel wall. In order to deter conduction of heat from theultrasonically heatable stent material to the blood passing through theinterior of the stent, an insulative coating may be applied to theinterior surfaces.

[0104] Use of the Ultrasonically Heatable Stent to Heat a Site on aVessel Wall

[0105] In the absence of heat dissipation by blood flow or conduction,most soft tissues in the body experience an increase in temperature at arate of about 0.86° C. per minute when subjected to an ultrasound beamof 1 mHz at an intensity of 1 Watt/cm² (R. Williams in “Production andTransmission of Ultrasound,” Physiotherapy, pp. 5-7 (March/April 1987)).Generally, if higher ultrasonic frequency is applied, the temperature ofthe tissue will rise at a much faster rate. Also, if a bony or otherreflective interface is present to reflect the ultrasound waves backinto the nearby tissue, extremely rapid heating of the tissue canresult. The depth of penetration of the ultrasound signal and the amountof heating obtained with a particular stent of the present invention isadjusted primarily by tuning the frequency of the ultrasound signals andby choice of placement of the transducers.

[0106] A highly preferred use of an ultrasonically heatable endoarterialstent, as exemplified above, is for implantation into a vessel and heattreatment of an angioplasty or atherectomy site. The new stent may beused for the heat treatment of a site of vessel wall injury to reducethe likelihood that restenosis will occur, similar to the methodsdescribed in U.S. Pat. No. 5,906,636 (Casscells et al.), the disclosureof which is incorporated herein by reference. The stent is deployed inaccordance with established clinical procedures for endolumenal stentplacement to achieve vascular patency, for example, in combination withor after balloon angioplasty. Following placement of the stent,ultrasound is focused on the stent from one or more ultrasoundtransducers that are positioned outside of the body and are situatedadvantageously for optimizing the ultrasound signal. Alternatively,three-dimensional ultrasound may be used to focus ultrasound beamscircumferentially about the stent, to optimize and more uniformly warm acylindrical section of vessel wall surrounding the stent. In eithercase, the surrounding vascular tissue is warmed at 38-42° C. for aperiod of time ranging from 550 minutes, depending on the particularshort-term or long-term therapeutic goal. For example, for the purposeof reducing post-injury inflammation, such as after balloon angioplasty,it is preferred to initially treat the injured tissue at 39-41° C.,whereby it shuts down macrophage production of cytokines, among otherinflammation-reducing effects.

[0107]FIG. 12 shows the temperature ranges over which several reversibleand irreversible effects on macrophages in atherosclerotic plaques areexpressed. These anti-inflammatory effects include expression of heatshock proteins (HSPs), apoptosis, cellular activity and necrosis. Eachof these macrophage effects is represented in Figutr 12 as an ellipticalor tapered shape so as to show the range and approximate peak ofactivity over the approximately 38-44.5° C. temperature range. Theinventors have observed that increasing temperature up to 40-41° C.reversibly shuts down macrophage activity, primarily due to expressionof heat shock proteins. Beyond that temperature range, apoptosispredominates, peaking near 43° C. At temperatures above about 43° C. themacrophages proceed to necrosis, which is an irreversible outcome.Overall, macrophage activity decreases after 39-40° C. These datastrongly suggest that inflammatory cells, particularly macrophages, havea unique “thermostat” or temperature-induced response mechanism which isdifferent from the typical temperature-induced responses of other kindsof cells. It is via this “different” mechanism that the body employsnegative feedback to limit inflammation and injury to adjacent cells byinducing excess oxidation and fever. This proposition goes against thegenerally held view that inflammatory cells necessarily have a very highheat threshold, since they need to function in high stress situationslike elevated temperature (fever) and in defensive mode againstinfectious agents, for example. The inventors' studies also stronglysuggest that various stress effects, including increased oxidativestress, appear to be additive in the response of macrophages ofatherosclerotic plaque and account for the greater sensitivity ofmacrophages to gentle heat than other cells. Therefore, by heating avessel site up to 42° C., deactivation of macrophages occurs andvulnerable plaque can be made more stable. The same concept is true forneointimal formation and smooth muscle cell proliferation in restenoticlesions that are inflammation driven, with macrophage infiltrationplaying a role.

[0108] In certain applications it is desirable to induce apoptosis incells other than macrophages. In the case of inducing cellular apoptosisprimarily in smooth muscle cells of an in-stent lesion, for instance, itis preferred to warm the stent at 42-43° C. for at least 15 minutes.Heating at 42° C. for 15-30 minutes inhibits the proliferation andregrowth of smooth muscle cells and also regresses or reduces the amountof cells and tissue for an extended period of time. This is accomplishedwithout inducing necrosis and the consequential inflammatory response tonecrotic bodies, and without incurring injury resulting from release oflysozomal enzymes. Lysozomal enzyme s digest extracellular matrix andcause further injury. Use of an ultrasound heated stent to achieve theabove-described heating protocols offers a different approach to thoseof conventional methods of heating atherosclerotic lesions for thepurpose of killing cells or fusing proteins.

[0109] Since preconditioning of cells through pre-heating (even atsub-apoptotic temperatures) can protect or “innoculate” the cellsagainst apoptosis, it is best to refrain from applying apoptotic thermaltreatment until at least 48-72 hours after a prior heat treatment. Thisis true for inducing apoptosis in macrophages or in other cell types.

[0110] During heating cycles, the wave frequency, intensity and durationof the ultrasound are adjusted by the operator, based on preestablishedcalibration data for the ultrasound system, on the acoustic impedancecharacteristics of the particular coat composition selected, and,optionally, on temperature measurements, if available. In this way,heating of the stent is optimized and unwanted heating of theintervening tissue is minimized, preventing tissue in the path of theultrasonic beam from being damaged or excessively heated before thestent reaches the desired temperature. Once a desired temperature isreached in the stent coating using continuous wave ultrasound, the usercan change to pulsed US to maintain that temperature. Alternatively, theapplied power can be adjusted to regulate the temperature. Low intensityultrasound is preferred, in a range near to that employed in diagnosticultrasound procedures, so that the methods described herein can be morewidely implemented due to the ready availability of diagnostic rangeultrasound equipment. The intensity of the ultrasound should not beexactly the same as the intensity used for conventionalechocardiography, however. This prevents any spurious heating of theultrasound heatable stent that might occur during relatively short termechocardiography procedures. Undesirable heating during routineechocardiography is even less likely due to the fact that no focusing ofthe ultrasound beam is customarily employed in echocardiography, and therelatively wide beam has little impact on the ultrasound heatable stentsof the invention. Although low intensity ultrasound is preferred, ifmore than about 15 minutes heating time is required to sufficiently warma stent (for example, to reach 42° C.), the power may be adjusted to midor high intensity range. If the depth of penetration of the ultrasoundsignal and the amount of reflective heating can be adequately regulated,the ultrasound heatable coating may be omitted. Under well-controlledconditions, the tissue adjacent the US-reflective metal stent can becarefully heated using reflected US, although this method is lesspreferred than methods employing the US heatable coated stents becauseof the difficulty in controlling the extent of heating. In order to getthe best vessel wall heating characteristics, it is best to constructthe stent in such a way as to provide optimal reflection.

Temperature Measurement by Remote Ultrasound

[0111] As discussed above, the acoustic impedance of a given medium isequal to the product of the density of that medium and the speed ofsound therein. The speed at which ultrasound travels through a mediumalso varies with the temperature of the medium. It is thischaracteristic that makes it possible to remotely measure thetemperature of a medium using ultrasound.

[0112] In living human tissue the speed of sound increases byapproximately 0.08% per degree centigrade and the density decreases byapproximately 0.04% per degree centigrade over the applicabletemperature range of about 35-50° C. This results in a change of theacoustic impedance of about 0.04% per degree centigrade. It is thereforepossible to measure temperature of a locus based on the acousticimpedance of the tissue undergoing examination.

[0113] Methods for the non-invasive, non-destructive measurement of theacoustic impedance present in the inside of a subject are well known inthe art of medical ultrasound technology. For example, U.S. Pat. No.5,370,121 (issued to Reichenberger, et al.) describes a method of usingultrasound to measure temperature changes over time in a tissue, such asa tumor undergoing hyperthermic treatment to cause necrosis of theheated tissue. U.S. Pat. No. 4,513,749 (Kino, et. al.) describes athree-dimensional temperature probe for measuring temperature within alocalized region of the body. Maass-Moreno et al. (J Acoust Soc Am100:2514-21 (1996) describe another noninvasive method of estimatingtemperature in tissue based on ultrasound echo-shifts. Accordingly, thetemperature of the stent or the adjacent tissue is monitored by one ofthese established non-invasive techniques.

[0114] The particular temperature or heating range chosen should besufficient to reduce inflammation or to induce apoptosis in inflammatorycells of an existing inflamed atherosclerotic plaque, without causingnecrosis in the tissue, following a rationale substantially as taught byCasscells et al. in U.S. Pat. No. 5,906,636 and illustrated in FIG. 12.A preferred treatment regimen includes initially placing the coatedstent over a recent angioplasty site. After externally positioning oneor more ultrasound transducers, the temperature of the coated stent isgradually raised via ultrasound waves to about 38-41° C. Thistemperature range is maintained for a sufficient time to producetemporary intracellular anti-inflammatory effects within the macrophagecells at the site, release of inflammatory signaling factors (cytokines)and/or anti-proliferative effects within the smooth muscle cells at thesite. Such treatment is aimed at reducing or eliminating residualinflammation from the treatment site. Subsequently, and particularlywhen reduced blood flow through the stent is detected, the temperatureof the coated stent is raised via ultrasound to about 42-42° C.,preferably 42° C. for at least 15 minutes. This higher temperaturetreatment is maintained for a sufficient time to produce permanentanti-inflammatory and/or anti-proliferative cellular effects, includingapoptosis. Further heat treatments at similar temperature and durationranges are optionally applied later, as deemed medically necessary, todeter recurrence of inflammation at the site and/or to inhibit or reduceinstent restenosis.

[0115] In order to avoid possible reflection of ultrasound by hardtissue (bone), the ultrasound waves can be introduced bytrans-esophageal approach in which a transducer is located inside theesophagus, similar to the trans-esophageal echocardiography (TEE)procedure. The transducer can thusly be positioned very close to theheart, permitting heating of the stent and ultrasound wave penetrationparameters to be more easily optimized. It can also be inserted betweentwo ribs in the intercostal space so that the chance of bone reflectionis minimized.

[0116] Another way of ultrasonically heating the implanted stent is tointroduce an intravascular ultrasound (IVUS) transducer into the vessellumen and to irradiate the stent from inside. This mode of treatment(which places the ultrasound source much closer to the stent than ispossible with external procedures) might be preferred under certaincircumstances, particularly if it can be combined with another invasivecardiovascular procedure.

[0117] In contrast to other ultrasound based heating methods, which areused primarily for thermal therapy of tumors or other large areas oftissue, the present method does not rely on direct absorbance ofultrasound waves by the tissue to achieve heating. Instead, the presentmethod heats the tissue primarily by conduction of heat out of theultrasonically heated stent coating material. The stent of the presentinvention is expected to be especially useful for gently heating smallregions of vessel wall tissue, particularly vascular sites where aplaque has undergone angioplasty or atherectomy. This gentle, or lowgrade heating of vessel tissue closest to and surrounding the stent to38-42° C. is accomplished as the coated stent experiences a 1-5° C.temperature rise above ambient vessel temperature due to the ultrasoundirradiation. Other types of vessel wall conditions that might benefitfrom similar treatment include vasculitis of great vessels like Takayasusyndrome, which narrows the orifice of central arteries such as thecommon carotid and subclavian. It might also be applicable to patientswith renal artery stenosis, which is the major cause of secondaryhypertension in children and adolescence. Another possible applicationis treatment of a cancerous tumor by sealing the feeding artery usingnon-invasive focused ultrasound to heat only a plastic stent implantedinside the artery. In this case a plastic stent should be designed so asto melt and occlude or seal the artery, producing effects similar tothromboembolization of a tumor artery. One difference between thepresent method and conventional high intensity focused ultrasoundtechniques is that the latter method is intended to burn the whole tumortissue. However, because it is not possible to clearly define the marginof a tumor, there is almost always some remnant.

[0118] By appropriately modifying the ultrasound heatable stents of thepresent invention, a similar treatment regimen can be applied to treatluminal cancer tissue such as bladder, neck, prostate, as well asintestinal lumen and billiary duct cancers. If temperatures higher thanabout 42° C. are required for a particular application, the choice andthickness of the ultrasound-absorptive coating material is merelymodified. Greater heat generation is produced with thicker coatingshaving higher acoustic impedance characteristics and by reflection dueto the presence of a higher-absorbing acoustic material. Of course theultrasound-absorptive materials selected must also be chemically stableat the higher temperatures, such as those commonly employed fortreatment of cancer and other pathophysiological conditions.

[0119] An alternative use of the ultrasonically heated stents of theinvention for treating infected, or possibly infected stents to reduceor eliminate the infection. Another alternative application of the newUS-sensitive coated stents is for performing non-invasive thrombolysisof endolumenal clots. In this embodiment, a focused ultrasound beam isdirected obliquely onto the stent in such a way that the stent reflectsultrasound waves into the clot.

Ultrasonic Heating of a Synthetic Vascular Graft

[0120] Having established that materials with different acousticimpedances have corresponding differences in their rate of heating, andthat these characteristics can be used to advantage to cause gentle orlow grade heating of body tissue, the inventors will examine additionalbiocompatible polymers or plastics to identify therapeutically usefulones that are susceptible to ultrasonic heating. Oftentimes afterimplantation of a graft, such as an arterio-venus (AV) graft,inflammatory cells accumulate inside the graft lumen. This is due, atleast in part, to the injury resulting from the surgery (implantation),and also to the fact that the graft, even though made of “biocompatible”material is still a foreign body which minimally stimulates immunecells. Also, in the case of AV grafts, because of the disturbed bloodflow, it induces local intimal injury adjacent the graft where it meetsthe vein. Accumulation of inflammatory cells, overgrowth of vasculartissue, and clots leads to AV graft stenosis. A population ofinflammatory cells is reduced or eliminated without invasive measures byapplying external low intensity ultrasound to the graft. The ultrasoundirradiation is such that the graft material becomes heated to atemperature in the range of 39-42° C., for example, for a period of timesufficient to induce apoptosis in the inflammatory cells.

[0121] Another type of synthetic graft that is subject to an influx ofinflammatory cells and to blockage due to thrombus formation is thearterio-venous hemodialysis shunt. Since arteriovenous hemodialysisshunts are relatively superficially located, an ultrasound-heatableshunt is readily heated up using ultrasound diathermy. Ultrasounddiathermy, similar to that used in physical therapy, provides 2-3 cmsignal penetration, which is adequate to warm an arteriovenoushemodialysis shunt made of suitable ultrasound sensitive material by1-5° C., at least. As is the case with endolumenal stents, describedabove, inflammatory cells that have migrated into the hemodialysis shuntare reduced or eliminated by the heat treatment.

Use of the Ultrasonically Heatable Stent for Periodic Local DrugDelivery

[0122] In some treatment modalities it would be beneficial to have adrug entrapped by a heat sensitive, ultrasound heatable polymer coatingon a stent, or other implanted medical device. With such a coateddevice, measured aliquots of a drug could be released as desired bydirecting an external ultrasound source toward the stent, or otherdevice, to heat the coating and release the drug. A drug, such as ananti-inflammatory drug, is incorporated into the matrix of apolymer-coated stent for periodic release at a stent implantation siteby action of an external ultrasonic trigger. The coating material is aUS-heatable polymer that releases a portion of the drug upon beingheated to a threshold temperature, whereby the permeability of thepolymer increases and a quantity of the drug is released at the stentedregion of the vessel wall. Once the ultrasound is turned off and thetemperature of the device is allowed to return to ambient bodytemperature, the polymer returns to its less drug permeable state. Asneeded, the stent can later on be heated again, via ultrasound, torelease additional drug.

[0123] Alternatively, the drug of interest is contained inheat-sensitive liposomes that are injected into the blood stream. Uponheating the stent ultrasonically, as described above, the drug isreleased from the liposomes as they reach the “hot spot” in the vesselconstituting the stent location. In this case, the area of interest fordrug delivery can be downstream of the artery or the whole heart muscle.Stent heating is of short enough duration that significant heating ofthe blood is not produced.

[0124] While preferred embodiments of the invention have been shown anddescribed, modifications thereof can be made by one skilled in the artwithout departing from the spirit and teachings of the invention. Theembodiments described herein are exemplary only, and are not limiting.Many variations and modifications of the invention disclosed herein arepossible and are within the scope of the invention. Accordingly, thescope of protection is not limited by the description set out above, butis only limited by the claims which follow, that scope including allequivalents of the subject matter of the claims.

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What is claimed is:
 1. An ultrasonically heatable stent comprising atleast one ultrasound-absorptive material characterized by an acousticimpedence greater than that of living soft tissue.
 2. The stent of claim1 further comprising: a stent framework configured to maintain patencyof a human vessel, and a coating comprising said at least oneultrasound-absorptive material overlying said stent framework andcharacterized by being heatable by ultrasound at a faster rate thanliving soft tissue.
 3. The stent of claim 2 wherein said stent frameworkis wire mesh.
 4. The stent of claim 2 wherein said at least oneultrasound-absorptive material has a heating rate greater than 0.86° C.per minute when subjected to an ultrasound beam of 1 mHz frequency and 1Watt/cm² intensity.
 5. The stent of claim 1 wherein said at least onematerial is a polymer.
 6. The stent of claim 5 wherein said polymer ischosen from the group consisting of silicone, polyvinylchloride,polyurethane, nylon, phosphorylcholine and combinations thereof.
 7. Thestent of claim 2 wherein said coating further comprises aheat-releasable drug.
 8. The stent of claim 2 wherein said coatingcomprises at least two ultrasound-absorptive layers, one said layeroverlying at least one other layer, said layers having dissimilaracoustic impedance characteristics and together enhancing theultrasound-induced temperature increase of said stent when exposed toultrasound.
 9. The stent of claim 2 wherein said coating ischaracterized by a temperature increase of 15° C. in response toultrasound irradiation.
 10. The stent of claim 2 wherein said stent isconfigured to contact a region of vessel wall, and said coating isfurther characterized by having an acoustic impedance greater than thatof any intervening tissue between said stent and an external ultrasoundtransducer, when said stent is situated in a vessel and ultrasonicradiation is directed onto said stent.
 11. A method of making anultrasonically heatable stent comprising: obtaining a stent frameworkconfigured for maintaining patency of a vessel; obtaining abiocompatible coating material characterized by having an acousticimpedance greater than that of human soft tissue; applying a coating ofsaid material to said stent framework, said coating being of suchthickness and character that said stent is heatable by ultrasound at afaster rate than human soft tissue.
 12. The method of claim 11 whereinsaid obtaining a biocompatible coating material comprises choosing amaterial from the group consisting of silicone, nylon,polyvinylchloride, polyurethane, phosphorylcholine, and combinationsthereof.
 13. The method of claim II wherein said step of obtaining abiocompatible coating material includes choosing a material having aheating rate greater than 0.86° C. per minute when subjected to anultrasound beam of 1 mHz frequency and 1 Watt/cm² intensity.
 14. Themethod of claim 11 wherein said step of applying a coating of saidmaterial to said stent framework comprises applying at least two layersof coating material, each said layer chosen from the group of materialsconsisting of silicone, polyvinylchloride, nylon, polyurethane,phosphorylcholine, and combinations thereof, said coating being of suchthickness and character that said stent is heatable by ultrasound at afaster rate than human soft tissue whereby a temperature about 1-5° C.above ambient temperature is induced in said stent.
 15. A method oftreating an atherosclerotic plaque in a living subject comprising:obtaining the ultrasonically heatable stent of claim 1; positioning saidstent in a vessel lumen so as to contact a region of vessel wallcomprising an atherosclerotic plaque; advantageously positioning atleast one ultrasound transducer external the body of said subject; andoperating said ultrasound transducer such that an ultrasonic beam isdirected at said stent, whereby the temperature of said stent ismaintained at about 1-5° C. above ambient temperature for a sufficientperiod of time to heat said region of vessel wall at a temperature of38-42° C.
 16. The method of claim 15 further comprising: measuring thetemperature of said region of vessel wall; and employing amicroprocessor and visual display system to control the operation ofsaid ultrasound transducer and to receive, analyze and display saidtemperature measurements.
 17. The method of claim 15 wherein saidultrasonic beam is directed using an acoustic lens to focus theultrasound beam.
 18. The method of claim 15 wherein two or moreultrasound transducers are advantageously positioned external the bodyof said subject and wherein said ultrasound transducers are operated incooperation such that at least two ultrasonic beams are directed at saidstent.
 19. The method of claim 15 wherein said step of advantageouslypositioning an ultrasound transducer external the body of said subjectis omitted and the step of positioning at least one transducer insidethe esophagus.
 20. The method of claim 15 wherein said step ofadvantageously positioning an ultrasound transducer external the body ofsaid subject is omitted and the step of positioning an intravascularultrasound transducer inside said stent is substituted therefor.
 21. Amethod of treating a vascular injury comprising: obtaining theultrasonically heatable stent of claim 1; positioning said stent in avessel lumen so as to contact a region of vessel wall comprising anendoluminal vascular injury in need of treatment; advantageouslypositioning an ultrasound transducer inside said stent; and operatingsaid ultrasound transducer such that an ultrasonic beam is directed atsaid stent, whereby the temperature of said stent is maintained at about1-5° C. above ambient temperature for a sufficient period of time toheat said region of vessel wall at a temperature of 39-40° C.
 22. Themethod of claim 21 wherein said step of positioning said stent in avessel lumen comprises positioning said stent at an angioplasty oratherectomy site.
 23. The method of claim 21 further comprising:subsequent to said 39-40° C. maintaining step, detecting restriction ofblood flow through said stent; and operating said ultrasound transducersuch that an ultrasonic beam is directed onto said stent, whereby thetemperature of said stent is maintained at a temperature about 1-5° C.above ambient temperature for a sufficient period of time to heat saidregion of vessel wall at 42° C. for 15-30 minutes.
 24. A method ofreducing or eliminating a population of inflammatory cells on animplanted synthetic vascular graft in a living subject comprising:advantageously positioning an ultrasound transducer external the body ofsaid subject; and operating said ultrasound transducer such that anultrasonic beam is directed at said synthetic vascular graft, wherebythe temperature of the graft, or a portion thereof, is increased to andmaintained at about 1-5° C. above ambient vessel temperature for asufficient period of time to heat said graft or portion thereof at atemperature of 38-42° C., provided that said synthetic graft contains anultrasound-absorptive material characterized by an acoustic impedancegreater than that of human tissue and that is chemically stable . whenheated up to about 45° C.
 25. A method of inhibiting or regressingin-stent restenosis comprising: implanting the ultrasonically heatablestent of claim 1 into a vessel of a subject; advantageously positioningan ultrasound transducer external the body of said subject; andoperating said ultrasound transducer such that an ultrasonic beam isdirected at said stent, whereby the temperature of the stent isincreased to and maintained at about 1-5° C. above ambient vesseltemperature for a sufficient period of time to heat said stent at atemperature of 41-42° C.